Process for the production of 6alpha-fluorocortisone and intermediates therein



United States Patent 3,084,157 Patented Apr. 2, 1963 "ice 3,084,157 PROCESS FDR THE PRGDUCTION 0F 6a-FLUORO- CGRTISSNE AND INTERMEDIATES THEREiN Howard J. Ringold, Albert Bowers, Octavio Mancera, and George Rosenlcranz, all of Mexico City, Mexico, as

The present invention relates to cyclopentanophenanthrene compounds and a process for the production thereof.

More particularly the present invention relates to a. novel process for the production of the fia-fiuoro-cortisone, an active anti-inflammatory cortical type hormone starting from the Zhesters of l6a,l7a-oXido-A pregnen- 3[3,21-diol-1l,20-dione and to certain novel intermediates.

In the US. patent application of Djerassi, Halpern and Mancera, Serial No. 765,056, filed October 3, 1958, there is disclosed the production of the 2l-estei s (for example the acetate) of 16a,l7a-oxido-M-pregnen-BBJlediol l1, 20-dione. In accordance with the present invention ithas been discovered that opening of the 1606,17lX-OXid0 groupof the acetate of 16a,17a-oXido-A -pregnen-3fi,21-diol-11,20-dione with hydrogen bromide gave the ZI-acet'ate of 165- bromo-A pregnen 3 3,17u,21 triol-11,20-dione and removal of the 165 bromo group with Raney nickel gave the ZI-aoetate of A -pregnen-3 8,l7oc,2l-tri0l 11,20 dione.- Treatment of this compound with formic acid followed by treatment with acetic anhydride produced the B-form-ate 17, ZI-diacetate which on partial saponifica-tion gave the 17,21-diacetate. The double bond of the 17,21-diacetate of A -pregnen-3/3,17a,21-triol-ll,2O-dioneon treatment with an aromatic peracid'was epoXidized to give the 17,21- diacetate of 5a,6a-oxido-pregnan-3fl,17a, 21-triol-11,20- dione. Treatment with boron trifluoride, oxidation :of the 3-hydroxy group, dehydration and inversion then gave the 17,2l-diacetate of 6a-fluorocortisone which was conventionally saponified. I V

The following equation illustrates the process of the preesnt invention and novel intermediates:

01-120 R (EH20 R 10 .0 O V l :O I OH O: 0-

TBr i I no- IIO Rmey nickel, formic acid, acylation Y CH2OR OH2OR to 50 --o R --.-on r epoxidation O "T I arti no gapom H-C-O- fication v boron trifiuorido CHrOR oxidation l i I OH i OH F dehydration and inversion (H01) 0 Hz 0 H 0 Hz 0 R In the above equation R represents an acyl group of a hydrocarbon carboxylic acid of less than 12 carbon atoms conventional in the steroid art. These acyl groups may be saturated or unsaturated, straight or branched chain aliphatic, cyclic or mixed cyclic aliphatic. Typical are the acetate, propionate, benzoate and cyclopentylpropionate. It may he noted further that lower fatty acid esters such as acetic are especially desirable for use in the reaction.

In practicing the process of the invention above set forth, an ester preferably the 21-mono acetate of :,17aoXido-A -pregnen-3fl,2l-diol-l1,20-dione in an organic sol: vent such as methylene dichloride is reacted with hydro. gen bromide in acetic acid to obtain the corresponding 21- acetate of l6fl bromo-n -pregnen-3fi,17u,21-tri-ol-11,20- dione. This compound is then treated with Raney nickel in a lower aliphatic alcohol under reflux conditions to re move the 16-brorno and substitute hydrogen therefor. The resultant 2l-acetate of A -pregnen-35,17a,21-triol-11, ZO-dione was then treated with formic acid to form the corresponding 3-forrnate-2l-acetate. Treatment of this diester with an excess of lower fatty acid anhydride preferably acetic and preferably inthe presence of an acid catalyst such as p-toluenesulfonic acid then produced the 3-formate-17,21-diacetate of A -pregnen-3/3,17a,21-triol- 11,20-dione. This triester'was then partially saponified with acid to produce the 17,2l-diacetate and treatment of the diacetate with an aromatic peraoi-d gave the 17,2l-diacetate of 5a,6u-oXido-pregnan 3 fl,l7u,21 triol-l 1,20-dione. Treatment of this compound with boron trifiuoride preferably in the form of its etherate under the conditions more completely outlined in our US. patent application Serial No. 753,629, filed August 7, 1958, gave as an intermediate the 17,21-diacetate of 6,8-fluoro-pregnan-3fi5a, 17a,21-tetrol-l1,20-dione.

The 3-hydroxy group of this compound was then conventionally oxidized to a 3-keto group and the resultant 17,21-diacet-ate of 6/3-fiuoro-pregnan-5u,17a,21-triol-3, 1 1, 2O-trior'1e was then treated with dry hydrogen chloride in acetic acid asdes-cribed in the aforementioned application to form the 17,21-diac'etate of 6a-fluoro-cortisone. Co'nventional saponification of this diester' gave the free compound.

The following specific examples serve to illustrate but are not intended to limit the present invention.

Example 1 A stirred solution of 7.5 g. of the 21-acetate of l6oc,l7aox1do-A -pregnen-3fl,2l-diol-l1,20-dione in 150 cc. of methylene dichloride was treated dropwise with 5.1 cc. of a solution of dry hydrogen bromide in acetic acid which was added in the course of 10 minutes. After the addition of water the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure below C. There was thus obtained the ZI-acetate of 16,3 bromo-A -pregnen-3 fi,17a,21-tli0l-1 1,20-dione. The analytical sample was obtained by recrystallization from acetone-hexane.

7.5 g. of the crude 21-acetate of 16fi-bromo-A -pregnen- 3fi,17a,2l-triol-11,20-dione was added to a suspension of 15 g. of Raney nickel in 300 cc. of methanol, the mixture was refluxed for 2 hours with stirring, cooled, filtered under an atmosphere of nitrogen and the residue was washed with methanol. The combined filtrate and wash. mgs was evaporated to dryness and the residue crystallized from acetone-hexane to produce the 21-acetate of A -pregnen-3fi,17a,21-triol-1 1,20-dione.

A suspension of 6 g. of the above compound in 150 cc. of 85% formic acid was stirred for 2 hours while heatmg to 70 C. and then cooled. The crystalline precipitate of the 3-formate-21-acetate of A -pregnen-3fi,17,2l-tri0l- 11,20-dione was collected by filtration.

A mixture of 5 g. of the above compound, 120 cc. of acetic anhydride and 1.7 g. of p-toluenesulfonic acid was stirred at room temperature for 9 hours and then poured into a mixture of ice and water. The mixture was stirred to hydrolyze the excess of anhydride and the crystalline precipitate was collected, washed with water, dried and recrystallized from acetone-hexane, thus producing the 3- formate-17,21-diacetate of A -pregnen-3fi,l7u,21-triol- 11,20-dione.

A solution of 5 g. of the above triester in 150 cc. of dioxane was mixed with cc. of water containing 5 cc. of concentrated hydrochloric acid and stirred at room temperature for 8 hours. The mixture was poured into water and after keeping it overnight in the refrigerator the precipitate was filtered, washed with water, dried and recrystallized from acetone-hexane, thus giving the 17,21- diacetate of A -pregnen-3fi,17a,21-triol-11,20-dione.

A solution of 4 g. of the 17,21-diacetate of A -pregnen- 3fi,17a,21-triol-l1,20-dione in 80 cc. of chloroform was treated with 1.8 mols of perphthalic acid in ether, the mixture was kept standing at room temperature for 20 hours and then poured into water. The organic layer was separated, washed with water, sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Crystallization of the residue from acetone-hexane yielded the 17,21-diacetate of :,6ot oxido-pregnan- 318,17 a,21-triol-1 1,20-dione.

A solution of 3 g. of the 17,21-diacetate of 502,60:- oxido-pregnan-3fl,17a,21-triol-11,20-dione in 300 cc. of a mixture of equal parts of ether and benzene was treated with 3 cc. of boron trifluoride etherate. The mixture was kept for 3 hours at room temperature, water was added followed by 300 cc. of ether and the organic layer was separated and washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by chromatography on neutral alumina to give the 17,21-diacetate of 6fl-fiuoro-pregnan- 3fl,5a,17e,2l-tetrol-11,20-dione.

2 g. of the 17,2l-diacetate of 6 3-fiuoro-pregnan- 3fi,5a,17a,2l-tetrol11,20-dione was dissolved in 100 cc. of acetone, cooled to 0 C. and treated dropwise with stirring, while the temperature was maintained below 0 C., with a solution of 8 N chromic acid which had been prepared by dissolving 1.2 g. of chromic acid in concentrated sulfuric acid and diluted with water. The mixture was stirred for a further 5 minutes at 0 C. and then diluted with water and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Crystallization of the residue from acetone'hexane yielded the 17,21- diacetate of 6,8-fluoro-pregnan-5a,17a,21-triol-3,11,20- trione.

1.8 g. of the 17,21-diacetate of 6fi-fiuoro-pregnan- 5a,17a,21-trio1-3,11,20-trione Was dissolved in cc. of acetic acid and a slow stream of dry hydrogen chloride was introduced into the solution for 2 hours at a temperature of around 18 C. The solution was poured into ice water, the precipitate formed was filtered, washed with water, dried and recrystallized from acetone-hexane. There was thus obtained the 17,2l-diacetate of 6a-fiuorocortisone.

1 g. of the diacetate of 6a-fiuoro-cortisone was sus pended in 10 cc. of absolute methanol, cooled to 0 C. and mixed with a methanol solution of sodium methoxide prepared by dissolving mg. of sodium metal in 10 cc. of absolute methanol. The addition was done dropwise at 0 C. with stirring under at atmosphere of nitrogen. The stirring Was continued for one hour further at 0 C. and the mixture was then poured into 100 cc. of an ice cold saturated solution of sodium chloride containing 0.5 cc. of acetic acid. The precipitate was collected, washed with water and recrystallized from acetone, thus furnishing 6a-fiuoro-cortisone.

We claim:

1. A method for preparing fia-fiuoro-cortisone, comprising opening the epoxide ring of the 2l-acetate of 16a,17a-oxido-A -pregnen-3{3,21-diol-11,20-dione by reac' tion with hydrogen bromide to form the 2l-acetate of 16 3-bromo-A -pregnen-3;8,17a,21-triol-l1,20-dione, substituion of the bromine of this bromohydrin by hydrogen by treatment with Raney nickel to obtain the ZI-acetate of A pregnen-3/3,1'7a,21-trio1-11,20-dione, reacting this last compound with acetic anhydride to form the 17,21- diacetate thereof, epoxidation of the double bond of the 17,21-diacetate to produce the t17,21-diacetate of 5a,6aoxido-pregnan 3}3,'17u,21 triol-l1,20-dione, opening of epoxide ring of the last compound by reaction with boron trifiuoride etherate to form the l7,2il-diacetate of 6fl-fiuoro-pregnan-3fl,5a, l7a,21-tetrol-1 l,20dione, oxidation of the hydroxyl group at 0-3 of this compound, dehydration of the resulting 17,21-diacetate of p-fluoropregnan-Sa,l7a,21-triol-3,11,20-trione, with simultaneous inversion of the steric configuration at C-6 by reaction with hydrogen chloride in acetic acid, to obtain the 17,21- diacetate of 6a-fiuoro-cortisone, and saponification of the latter to the free fia-fluoro-cortisone.

2. A method for the production of the 17,2l-di lower fatty acid acylate of 5a,6a-oxido-pregnan-3/3, 17a,2l-triol- 11,20-dione comprising treating a 21-lower fatty acid ester of l601,17u-oxido-A -pregnen-3fl,2l-diol-l1,20-dione with hydrogen bromide to form the corresponding 21-lower fatty acid ester of l6fi-bromo-A -pregnen- 313,170L,2J1-t1'i01-1LZOdlOIIe, removing the 16-bromo group of the last mentioned compound to form the 21-lower fatty acid ester of A -pregnen-3fl,17a,21-trio1-l1,20-dione by reaction with Raney nickel, reacting the last mentioned compound with formic acid to form the 3-formate-21- lower fatty acid acylate thereof, reacting the last mentioned compound with a lower fatty acid anhydride to form the 3-formate-17,21-di lower fatty acid acylate, partially saponifying this last mentioned compound to form the corresponding 17,21-diacylate and treating the diacylate with an aromatic peracid.

3. The process of claim 2 wherein the lower fatty acid acylate is acetate.

4. A 21-lower fatty acid ester of l6B-bromo-A -pregnen-3 S, 17a,21-trio1-11,20-dione.

5. The '21-acetate of 16fi-bromo-A -pregnen-3fi,170:,21- triol-l 1,20-dione.

6. The 17,-21-di lower fatty acid ester of 5a,6u-oxidopregnan-3fi, 17 (1,2 1-triol-1 1,20-dione.

5 7. The 17,21 diacetate of 501,60: oxido pregnan- 3 3, 17 a,21-trio1-1 1,20-dione.

8. The 17,21-di lower fatty acid ester of Gfi-fiuoropregnan-3B,5a,17a,21-tetro1-11,20-dione.

9. The 17,21-diacetate of 6fl-fluoro-pregnan-3flja,17a, ZI-tetrol-l 1,20-dione.

References Cited in the file of this patent UNITED STATES PATENTS 2,805,230 Stork et a1. Sept. 3, 1957 6 Hogg et a1. July 1, 1958 Rothman et a1 Apr. 21, 1959 Beal et a1. Aug. 11, 1959 Ringold et a1. Sept. 6, 1960 Rothman et a1 Aug. 29, 1961 

1. A METHOD FOR PREPARING 6A-FLUORO-CORTISONE, COMPRISING OPENING THE EPOXIDE RING OF THE 21-ACETATE OF 16A,17A-OXIDO-$5-PREGNEN-3B,21-DIOL-11,20-DIONE BY REAC TION WITH HYDROGEN BROMIDE TO FORM THE 21-ACETATE OF 16B-BROMO-$5-PREGNEN-2B,17A,21-TRIOL-11,20-DIONE, SUBSTOTUTUION OF THE BROMINE OF THIS BROMOHYDRIN BY HYDROGEN BY TREATMENT WITH RANEY NICKEL TO OBTAIN THE 21-ACETATE OF $5-PREGNEN-3B,17A,21-TRIOL-11,20-DIONE, REACTING THIS LAST COMPOUND WITH ACETIC ANHYDRIDE TO FORM THE 17,21DIACETATE THEREOF, EPOXIDATION OF THE DOUBLE BOND OF THE 17,21-DIACETATE TO PRODUCE THE 17,21-DIACETATE OF 5A,6AOXIDO-PREGNAN - 3B,17A,21 - TRIOL-11,20-DIONE, OPENING OF EPOXIDE RING OF THE LAST COMPOUND BY REACTION WITH BORON TRIFLUORIDE ETHERATE TO FORM THE 17,21-DIACETATE OF 6B-FLUORO-PREGNAN-3B,5A,17A,21-TETROL-11,20-DIONE, OXIDATION OF THE HYDROXYL GROUP AT C-3 OF THIS COMPOUND, DEHYDRATION OF THE RESULTING 17,21-DIACETATE OF 6B-FLUOROPREGNAN-5A,17A,21-TRIOL-3,11,20-TRIONE, WITH SIMULTANEOUS INVERSION OF THE STERIC CONFIGURATIONN AT C-6 BY REACTION WITH HYDROGEN CHLORIDE IN ACETIC ACID, TO OBTAIN THE 17,21DIACETATE OF 6A-FLUORO-CORTISONE, AND SAPONIFICATION OF THE LATTER TO THE FREE 6A-FLUORO-CORTISONE.
 6. THE 17,21-DI LOWER FATTY ACID ESTER OF 5A,6A-OXIDOPREGNAN-3B,17A,21-TRIOL-11,20-DIONE. 